Crabbe et al. JA Clinical Reports (2016) 2:31 DOI 10.1186/s40981-016-0058-1

CASE REPORT Open Access Therapeutic plasma exchange in transplantation: role of assessment with thromboelastometry Andrew Crabbe1, John S. McNeil2, Seema P. Deshpande1, Zachary Kon3, Si M. Pham3 and Kenichi A. Tanaka1*

Abstract Therapeutic plasma exchange (TPE) is a potentially life-saving procedure which effectively removes donor-specific human leukocyte antigen (HLA) antibodies from the bloodstream, allowing critically ill heart transplant recipients to receive a donor organ with less wait time, and reducing the risk of acute organ rejection. The bulk of coagulation factors is initially removed from the blood during TPE using albumin and is later replaced with allogeneic plasma. Coagulopathy may develop during TPE and then can persist due to intraoperative blood loss and hemodilution during surgery and cardiopulmonary bypass. We hereby describe the utility of rotational thromboelastometry to assess rapid coagulation changes during TPE and subsequent heart transplant (HT) surgery. Keywords: Coagulation, Plasma exchange, Fresh frozen plasma, Coagulation factor deficiency, Heart transplantation

Background thus routine at our institution to perform two plasma Therapeutic plasma exchange (TPE) is a procedure that volume exchanges using 5 % albumin, followed by an- is used to remove potentially harmful antibodies and other TPE with plasma. The loss of coagulation factors toxins from a patient. It is indicated for many disease during TPE is expected [8], but there is no strong evi- conditions including autoimmune anemia, autoimmune dence to support the superiority of plasma-only TPE vasculitis, hemolytic uremic syndrome, and multiple over albumin/plasma combination for non-surgical sclerosis [1]. TPE has been used in perioperative cardiac TPE indications [5, 9]. Perioperative TPEs using albu- surgical patients with antibodies relating to - min/plasma raise concerns about coagulation status be- induced thrombocytopenia [2], ABO incompatibility [3], cause a single TPE with plasma may be insufficient to and donor-specific human leukocyte antigen (HLA) [4]. fully restore hemostatic factor levels before the use of The latter antibodies (ABO and HLA) are pertinent to cardiopulmonary bypass (CPB). Rotational thromboe- organ donor matching, and transplant recipients may lastometry (TEM Innovations, Munich) was thus used suffer from long waits for organs due to incompatible to assess rapid coagulation changes during repeat TPEs antibodies. Perioperative removal of these antibodies via in this case of a patient with donor-specific HLA anti- TPE is feasible and often life-saving for critically ill bodies who underwent a heart transplantation. The aim organ recipients. of this report is to address the clinical implications of Albumin (5 %) is useful as an exchange fluid for serial TPE on coagulation and hemodynamic management in TPEs because of potential risks associated with a large the transplant recipient. amount of fresh frozen plasma (hereinafter referred to as plasma) [5]. In particular, allergic reactions can occur Case presentation in up to 40–65 % of patients undergoing multiple TPEs, A 43-year-old female, 66 kg, with non-ischemic cardio- although the severity of symptoms may vary [5–7]. It is myopathy (NICM) presented for HT. She was diagnosed with NICM 15 years ago, presumably related to preg- * Correspondence: [email protected] nancy and/or systemic lupus erythematous (SLE). Her 1Department of Anesthesiology, University of Maryland, 22 South Greene Street, Suite S8D12, Baltimore, MD 21201, USA past medical history included SLE with associated neph- Full list of author information is available at the end of the article ritis and vasculitis, insulin-dependent diabetes mellitus,

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previous pulmonary embolism, and previous stroke with potential for “euthyroid sick syndrome” exacerbated by residual visual field defects. TPE [11, 12]. The patient had been stable on a biventricular assist The transplant heart’s systolic function improved with device (BiVAD; HeartWare, Framingham, MA, USA) for the T4 infusion, and further mechanical support (e.g., 2 years while no HLA-matched donor was found despite veno-arterial extracorporeal membrane oxygenation) a 1b (moderate urgency) status. She was recently hos- was avoided. The patient remained stable in the intensive pitalized for worsening right heart function and was care unit (ICU), and the T4 infusion was weaned off along requiring increased inotropic support. Given the decline with other inotropes on postoperative day (POD) 2. In the in her clinical condition, the transplant team decided to ICU, four more sessions of TPE were performed to sustain use therapeutic plasma exchange (TPE), anti-lymphocyte the eradication of donor-specific antibodies; one plasma antibody treatment, and intravenous immunoglobulin volume exchange with FFP on POD 1 and 2, and one treatment in the perioperative period in order to accept plasma volume exchanged with 5 % albumin on POD 3 a cross-match positive donor heart [4, 10]. and 5 (plasma levels were above 150 mg/dL After an uneventful induction of anesthesia and line after TPEs). The patient was extubated on POD 5 and placement, a large dual lumen catheter was placed in the discharged from the hospital on POD 14. femoral and connected to the plasmapheresis device (Prismaflex® System, GAMBRO, Colorado). She under- Discussion went TPEs consisting of three plasma volume exchanges; Rotational thromboelastometry is a practical method to the first two exchanges used 5 % albumin (3300 ml each) assess rapid coagulation changes during surgery and to remove the HLA antibodies. The third plasma ex- CPB, and in this case report, it was used successfully change utilized 11 units of FFP to restore coagulation during multiple TPEs for heart transplantation (HT). factors for surgery. Throughout the procedure, coagula- [13]. Tissue factor-activated tests, EXTEM and FIBTEM tion status was assessed using tissue factor-activated (Table 1), are most useful in the acute setting because EXTEM and FIBTEM on rotational thromboelastometry extrinsic coagulation factors and fibrinogen, respectively, (Fig. 1). Baseline (pre-TPE) EXTEM and FIBTEM pa- are particularly prone to hemodilution and blood rameters were within normal range except for a high (plasma) losses [14, 15]. Clotting time (CT) of EXTEM FIBTEM-A10. After TPE with albumin, EXTEM-CT in- reflects prothrombin time (PT) sensitive coagulation fac- creased from 55 to 74 s. FIBTEM-A10 decreased from 34 tor levels [15], whereas 10 min amplitude (A10 clot firm- to 9 mm (−64.0 %) (Fig. 1a, b). TPE continued with FFP ness) reflects count and fibrinogen level [16]. (~35 ml/kg) during the explantation of the BiVAD device, FIBTEM better reflects plasma fibrinogen levels than and FIBTEM-A10 was 7 mm at the conclusion of this third EXTEM because its clot formation is specific due round of TPE (Fig. 1c). Measured plasma fibrinogen to the inclusion of cytochalasin D, a platelet inhibitor, in levels, which were reported approximately 25–45 min the reagent [16, 17]. after FIBTEM-A10 results were available, confirmed a net TPE is an important intervention for a variety of dis- loss of fibrinogen (Fig. 1a, c). eases that require the removal of undesirable toxins or The donor heart was implanted over 192 min of CPB antibodies. TPE potentially expands the donor pool for with a cross-clamp time of 93 min and a donor ischemic heart and lung transplants which otherwise can be lim- time of 256 min. After transplant and reperfusion, the ited by recipient antibodies to donor HLA. One to one patient was initially weaned from CPB with inotropic and a half plasma volume runs of TPE generally remove support (epinephrine 0.06 μg/kg/min and norepinephrine 63–78 % of alloantibodies (mostly IgG class), and three 0.03 μg/kg/min). Diffuse microvascular bleeding was at- TPEs can reduce these antibodies by 90 % [18]. In con- tributed to thrombocytopenia (EXTEM-A10, 31 mm) and junction with immunosuppressive agents, TPE can sig- low fibrinogen (FIBTEM-A10, 7 mm) (Fig. 1c). One pool nificantly reduce the risk of both acute and chronic of five single donor and 20 units (four pools) of allograft organ rejection [4]. Reduced FIBTEM values cryoprecipitate were transfused, and improved hemostasis correlate with the substantial removal of large plasma was observed in the surgical field in conjunction with nor- proteins (IgG, 150 kDa, and fibrinogen, 340 kDa) at the malized EXTEM and FIBTEM A10 values (Fig. 1d). end of albumin TPE [8]. Loss of fibrinogen and other In the post-CPB period, systolic dysfunction persisted coagulation proteins during albumin TPE increase the on increasing doses of epinephrine and norepinephrine risk of bleeding, particularly after CPB, and thus allo- (up to 0.1 μg/kg/min) despite adding vasopressin geneic plasma is generally recommended for intraoper- (0.06 units/min) and milrinone (0.375 μg/kg/min). ative TPEs [2]. However, full recovery of fibrinogen is Levothyroxine (T4;20μg/kg bolus, followed by 5 μg/ unlikely even if plasma-only TPE is used [5, 9], and kg/h infusion) was added to treat “stunned” myocar- CPB-induced hemodilution further decreases plasma fi- dium due to the long ischemic time as well as the brinogen [17]. Post-CPB fibrinogen levels below 200 mg/dL Crabbe et al. JA Clinical Reports (2016) 2:31 Page 3 of 5

Fig. 1 a Key parameters of EXTEM-CT: clotting time (s) [normal, 43–82 s], EXTEM-A10: 10 min amplitude (mm) [normal, 43–65 mm], and FIBTEM-A10 [normal, 9–24 mm]. b–d EXTEM and FIBTEM changes during and after therapeutic plasma exchange (TPE). Baseline fibrinogen was in supra-normal range (b), but it extensively decreased after TPE with albumin (c) and even after plasma replacement during surgery. Fibrinogen was restored only after the transfusion of cryoprecipitate (d) Crabbe et al. JA Clinical Reports (2016) 2:31 Page 4 of 5

Table 1 Types of assays on rotational thromboelastometry Test TF Contact Heparin effect Detectable condition(s) Hemostatic interventions EXTEM + −a Extrinsic pathway, PLT count, Plasma, PCC, or PLTs FIBTEM + −a Fibrinogen levelb Cryo or fibrinogen conc. APTEM + −a Systemic fibrinolysisc INTEM + + Intrinsic pathway, PLT count, fibrinolysis Plasma, protamine, or PLTs HEPTEM + −a Heparin effect Same as INTEM ACT activated clotting time, Cryo cryoprecipitate, Fibrinogen conc. fibrinogen concentrate, PCC prothrombin complex concentrate, PLT platelet, TF tissue factor activator, Contact contact activator (ellagic acid) aHeparin is neutralized by the reagent at concentrations up to 4–6 U/ml on EXTEM/FIBTEM/APTEM and 8 U/ml on HEPTEM bConfirmatory test for hypofibrinogenemia; low clot firmness (amplitude) on other ROTEM® tests may indicate either thrombocytopenia or hypofibrinogenemia cConfirmatory test for fibrinolysis; fibrinolysis may be shown on all the other ROTEM® tests

(FIBTEM-A10 <10 mm) are associated with an in- low probability of or a long wait before receiving a creased risk of bleeding and higher transfusion require- donor organ. In these patients, thromboelastometry ment [19, 20], and the restoration of fibrinogen to throughout the perioperative period can allow for a fast >250 mg/dL (FIBTEM-A10 > 15-18 mm) appears to reduce detection of coagulopathy and targeted component such risks [21]. We initially calculated the required therapy [25, 29]. amount (g) of fibrinogen using the published formula Funding below based on the FIBTEM-A10 value [21–23]: None.

FibrinogenðÞ g ¼½Štarget FIBTEM‐A10ðÞmm – current FIBTEM‐A10ðÞmm Authors’ contributions  weightðÞÄ kg 140 ¼ ðÞ15 mm – 7mm AC: This author managed the patient, collected the data, and wrote the manuscript. JM, SD, ZK, SP: These authors contributed to the patient care,  66 kg Ä 140 ¼ 3:77 g and helped write the manuscript.KT: This author managed the patient, and helped write the manuscript. All authors read and approved the final In the USA, clinical use of fibrinogen concentrate is manuscript. limited to hereditary afibrinogenemia and hypofibrino- genemia [24], and thus cryoprecipitate remains the Competing interests mainstay therapy for perioperative fibrinogen replace- Kenichi A. Tanaka is currently participating in a clinical study sponsored by TEM Innovations (Munich, Germany). All other authors declare that they have ment. The required amount (units) of cryoprecipitate no competing interests. can be estimated by multiplying the fibrinogen dose by five [25]; 3.77 × 5 = 18.9 units. Consent for publication After transfusing 20 units of cryoprecipitate, FIBTEM- Written informed consent was obtained from the patient for the publication of this report. A10 and fibrinogen were 16 mm and 276 mg/dL, respectively. Author details 1 Our case demonstrates the practical use of EXTEM Department of Anesthesiology, University of Maryland, 22 South Greene Street, Suite S8D12, Baltimore, MD 21201, USA. 2Department of and FIBTEM in monitoring perioperative changes in fi- Anesthesiology, University of Virginia, Charlottesville, VA, USA. 3Department brinogen levels and the therapeutic effects of cryopre- of Surgery, Division of Cardiothoracic Surgery, University of Maryland, cipitate (Fig. 1c, d) during TPE. It is also important to Baltimore, MD, USA. note that antibiotics (ceftazidime, tobramycin, etc.) and Received: 8 June 2016 Accepted: 11 October 2016 immunosuppressants (basiliximab) can also be elimi- nated by TPE [26, 27]. In addition, TPE is known to affect biologically active References 1. Winters JL. Plasma exchange: concepts, mechanisms, and an overview of hormones, including free thyroxine (T4) and triiodothyr- the American Society for Apheresis guidelines. Hematology. 2012;2012:7–12. onine (T3) [12]. Critically ill patients have limited re- 2. Roman PE, DeVore AD, Welsby IJ. Techniques and applications of serves of thyroid hormones [11], and there is some perioperative therapeutic plasma exchange. Current Opin Anaesthesiol. 2014;27:57–64. evidence to suggest that there is better preservation and 3. Issitt RW, Crook RM, Cross NT, Shaw M, Robertson A, Burch M, Hsia TY, function of the donor heart using T3 or T4 infusion [28]. Tsang VT. Incompatible ABO-plasma exchange and its impact on patient selection in paediatric cardiac transplantation. Perfusion. 2012;27:480–5. Therefore, T4 infusion may be potentially useful for the 4. Tinckam KJ, Keshavjee S, Chaparro C, Barth D, Azad S, Binnie M, Chow CW, management of stunned donor heart. de Perrot M, Pierre AF, Waddell TK, Yasufuku K, Cypel M, Singer LG. Survival in sensitized lung transplant recipients with perioperative desensitization. Conclusions Am J Transplant. 2015;15:417–26. 5. O'Brien KL, Price TH, Howell C, Delaney M. The use of 50 % albumin/plasma In conclusion, the use of TPE expands the donor organ replacement fluid in therapeutic plasma exchange for thrombotic pool to patients who otherwise would have an either a thrombocytopenic purpura. J Clin Apher. 2013;28:416–21. Crabbe et al. JA Clinical Reports (2016) 2:31 Page 5 of 5

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